Oxindole Inhibitors of Cyclin-Dependent Kinases as Anti-Tumor Agents

2016 ◽  
Author(s):  
Zuzana Skraškova ◽  
Radek Jorda ◽  
Eva Řezničkova ◽  
Vladimir Kryštof

Author(s):  
Shamim Mushtaq

Uninhibited proliferation and abnormal cell cycle regulation are the hallmarks of cancer. The main role of cyclin dependent kinases is to regulate the cell cycle and cell proliferation. These protein kinases are frequently down regulated or up regulated in various cancers. Two CDK family members, CDK 11 and 12, have contradicting views about their roles in different cancers. For example, one study suggests that the CDK 11 isoforms, p58, inhibits growth of breast cancer whereas, the CDK 11 isoform, p110, is highly expressed in breast tumor. Studies regarding CDK 12 show variation of opinion towards different parts of the body, however there is a consensus that upregulation of cdk12 increases the risk of breast cancer. Hence, CDK 11 and CDK 12 need to be analyzed to confirm their mechanism and their role regarding therapeutics, prognostic value, and ethnicity in cancer. This article gives an outline on both CDKs of information known up to date from Medline, PubMed, Google Scholar and Web of Science search engines, which were explored and thirty relevant researches were finalized.


2016 ◽  
Vol 13 (3) ◽  
pp. 234-242 ◽  
Author(s):  
Siripit Pitchuanchom ◽  
Chavi Yenjai ◽  
Chantana Boonyarat ◽  
Stefano Forli ◽  
Arthur J. Olson

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 550
Author(s):  
Indra A. Shaltiel ◽  
Alba Llopis ◽  
Melinda Aprelia ◽  
Rob Klompmaker ◽  
Apostolos Menegakis ◽  
...  

Most Cyclin-dependent kinases (Cdks) are redundant for normal cell division. Here we tested whether these redundancies are maintained during cell cycle recovery after a DNA damage-induced arrest in G1. Using non-transformed RPE-1 cells, we find that while Cdk4 and Cdk6 act redundantly during normal S-phase entry, they both become essential for S-phase entry after DNA damage in G1. We show that this is due to a greater overall dependency for Cdk4/6 activity, rather than to independent functions of either kinase. In addition, we show that inactivation of pocket proteins is sufficient to overcome the inhibitory effects of complete Cdk4/6 inhibition in otherwise unperturbed cells, but that this cannot revert the effects of Cdk4/6 inhibition in DNA damaged cultures. Indeed, we could confirm that, in addition to inactivation of pocket proteins, Cdh1-dependent anaphase-promoting complex/cyclosome (APC/CCdh1) activity needs to be inhibited to promote S-phase entry in damaged cultures. Collectively, our data indicate that DNA damage in G1 creates a unique situation where high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/CCdh1 to promote the transition from G1 to S phase.


Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1488
Author(s):  
Alessandra Ammazzalorso ◽  
Mariangela Agamennone ◽  
Barbara De Filippis ◽  
Marialuigia Fantacuzzi

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.


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